There are good reasons for investigating a medication as an anti-suicide treatment and studying suicidality as a primary indication. First, although suicide and suicidality are major and growing public health problems and suicide is now ranked as the 11th leading cause of death in the United States, the relationship between psychiatric medication and suicidality has not been well studied. Indeed, most of the work on medication and suicidality has been retrospective, confined to secondary post hoc analyses of single items on depression rating scales in registration trials pursuing other indications.
Second, although there is good evidence from clinical, epidemiologic and family populations that patients with mood disorders, including bipolar disorder I, II and NOS, have an elevated risk of suicide (1-2), there is growing evidence that vulnerability to suicidality may be inherited independently of vulnerability to mood disorders (3-8). These considerations have led to increasing calls for a separate category for “Suicide Disorders” in the Diagnostic and Statistical Manual of Mental Disorders V (DSM V).
Third, there is growing evidence that treatments that are effective for mood disorders are not always effective for suicidality and vice versa. Paradoxically, antidepressants, although they improve depression over 4 to 8 weeks, are not believed to lower suicidality. These findings highlight the need to find medications that work well for both symptomatic relief and suicidality.
Fourth, there is increasing evidence that suicidal risks vary across psychiatric medications. Today, all antidepressants, anticonvulsants and antipsychotics carry black box warnings in their product labeling, and all caution about the increased risk of suicidality on these medications compared to placebo. Preliminary evidence, however, suggests that all antipsychotics do not necessarily share the same suicidality risks and that some antipsychotics may actually lower the risk of suicidality in some disorders.
To date, no medication has been specifically approved by the U.S. Food and Drug Administration (FDA), or by other drug regulatory agencies, as an effective and safe treatment for suicidality, suicidal ideation or suicidal behaviors. Clozapine has been approved (“is indicated”) “for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state” (wording from Prescribing Information on Clozaril). However, in the context of growing concern about suicide in the United States, the FDA has recently expressed interest in reviewing any medication that might demonstrate efficacy against suicidality if suicidality is the a-priori primary outcome measure.
More than 32,000 people kill themselves each year. The increasing rates of completed and attempted suicide among veterans and active duty military is the subject of much media attention. In March 2009, the media reported that among U.S. troops, death by suicide outnumbered death in combat for two months in a row.
The World Health Organization estimates that in the year 2020 approximately 1.53 million will die from suicide. Ten to 20 times more people attempt suicide than complete suicide. This is an average of one suicide death every 20 seconds and one suicide attempt every 1 to 2 seconds (12).
Since 1950, when global suicide statistics were first collected, deaths from suicide have increased 49% in males and 33% in females. There has been a consistent but escalating three fold higher rate of successful suicides in males over females over time, ranging from 3.2:1 in 1960; 3.6:1 in 1995 to 3.9: in 2020 (12). This finding may be confounded by a larger number of countries reporting suicide statistics today than in 1950 (12). Attempted suicide is more common in females than in males. The female-male ratio for suicide attempts varies from 1.5:1 to 3:1 (13).
Approximately 10% of those admitted to hospitals following a suicide attempt eventually commit suicide. An additional 10% to 50% repeat their suicide attempts (13). After a suicide attempt, the danger of completed suicide is greatest in the first year and especially in the first 3 months after a suicide attempt (13). 90% of those who attempt suicide survive (13). Suicide attempts provide opportunities to identify and treat problems that would otherwise not come for treatment (13).
Suicide rates increase with age. In absolute numbers, most completed suicides in both men and women are between the ages of 35-45 years. The average global suicide rate for men is 24.7/100,0000 with a low of 0.9 per 100,000 for age group 5-14 years and increasing up to 66.9/100,000 in those over 75 years (12). The same increase with age is seen in females with an average rate of 6.9/100,000. This rate increases from 0.5/100,000 for the age group 5-14 years up to 29.7/100,000 in those over 75 years (12). There could be a significant increase in completed suicides in the next 15 years with the population bubble of baby boomers approaching the age of highest suicide risk. The highest suicide rates are in Eastern Europe (12).
The attempted suicide rate is higher in younger age groups than in older age groups. Conservative estimates suggest that attempted suicide is at least 10 times more common than completed suicide. The suicide attempt rate for males varies from 45-314 per 100,000 to 69-462 per 100,000 among females (13).
The largest twin study found a “concordance rate of serious suicide attempts in monozygotic twins of 23.1%” (4). This was more than a 70 fold greater risk than the risk in the total sample (4). The concordance rate for attempted suicide was higher than for completed suicide, suggesting that both attempted and completed suicide may he heritable. Adoptee studies found that the risk of suicides was transmitted from the biological family to the adoptee at birth, independent of the transmission of mood or psychotic disorders. Family studies suggest that the transmission of suicidal behavior is independent of the transmission of psychiatric disorders associated with suicidal behaviors (4, 6-8). The evidence suggests that the familial transmission of psychiatric disorders is independent of the familial transmission of genetic factors related to suicidal behavior (4, 6-8, 13).
Low levels of 5-Hydroxyindoleacetic acid (5-HIAA) in the cerebral spinal fluid (CSF) predict future suicide and suicide attempts. “Low levels of 5-HIAA in the CSF appears to be a biological index of vulnerability to suicidal behavior in several psychiatric disorders” (4). “The more lethal the suicidal behavior, the lower the level of 5-HIAA in the CSF” (4). Tryptophan hydroxylase is the enzyme “involved in the rate-limiting step in the synthesis of serotonin” (4). “Several studies found an association between a polymorphism in the tryptophan hydroxylase gene in intron 7 and suicidal behavior” (4). Those who make suicide attempts are different from those with the same psychiatric disorder but do not make suicide attempts by having more of the U-allele variant of this gene. This U-allele variant “is associated with lower levels of 5-HIAA in the CSF and a blunted prolactin response to funfluramine” (4).
The standard treatment approach for treating suicidal patients with recurrent unipolar major depressive disorder, bipolar depression and posttraumatic stress disorder, involves a combination of antidepressant medications, mood stabilizers and psychosocial treatments including cognitive behavior therapy.
Traditionally, it was assumed that the presence of suicidal ideation was driven by a depressive disorder and that when a depressive disorder was treated the suicidality would clear. Recent genetic studies suggest that, although suicidality and mood disorders frequently co-occur, there may be a different genetic vulnerability to each. All antidepressants now have “black box warnings” in their labeling indicating that there may be an increase in suicidal behaviors among some patients on antidepressants and that this needs to be monitored. Antidepressants are less effective against suicidality than was previously assumed (14). In bipolar depression, there is no evidence antidepressants are helpful (Sachs G. S. and Nierenberg A. N. et al. Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Disorder. New England Journal of Medicine April 2007. Number 17; 356:1711-1722).
In many bipolar patients, antidepressants increase rapid cycling and sudden mood switching, and increase the risk of suicidality. Lithium is the only medication that consistently reduces suicidality in recurrent unipolar major depressive disorder and in bipolar disorder (15). Balldesarini (16) found a 13 fold lower incidence of attempted and completed suicide in those on long-term lithium treatment compared to those who did not receive lithium. Balldesarini (17) found that the fatality rate due to suicide after discontinuing lithium was 12.6 times higher compared to the rate during lithium maintenance. These findings have not been investigated in a VA population.
In research on treatment in most specialties and disease states, the main contributors to mortality are usually the primary targets of treatment. Although suicide is the most important contributor to lethality in psychiatric disorders, it is almost never the primary target in treatment studies. This may be because of safety concerns or because of the absence, until recently, of suicidality measurements that inspire scientific confidence. A medication that lowers suicidality would represent a very welcome opportunity to lower mortality rates from suicide.